The present invention relates generally to nerve stimulation, and more particularly to cranial nerve stimulation to stimulate or enhance cardiac capillary growth and cardiac output in heart failure patients.
Heart failure is a cardiac condition or disorder characterized by an abnormal cardiac functionxe2x80x94specifically, low cardiac outputxe2x80x94that leaves the heart unable to meet the circulatory, oxygen replenishing needs of the body. An estimated 2 million or more individuals in the United States meet the clinical definition of heart failure, making this disorder a major health problem. Although some of the affected individuals are relatively symptom free, those with severe heart failure have very little physical endurance and may be bedridden. Heart rate is one of the major determinants of myocardial oxygen consumption.
It is customary to lower the patient""s heart rate as a method of treating heart failure. A lowered heart rate has the effect of improving the oxygen balance in the heart by reducing oxygen demand, while increasing supply through better coronary perfusion, particularly sub-endocardial, during a longer diastolic interval. This scheme is tolerable provided that the working capacity of the individual is not reduced to unacceptably low levels. Because of the complex control system linking heart rate via cardiac output to regulation of blood pressure and peripheral perfusion, most interventions resulting in long term bradycardia involve additional actions on the periphery through direct or indirect neuronal and/or hormonal mechanisms. Physiological bradycardia occurring with exercise training, and pathological bradycardia such as A-V block, are associated with activation of the sympathetic nervous and renin-angiotensin systems and enhanced catecholamine release. One effect of long-term bradycardia common to these situations is myocardial hypertrophy.
With pharmacological methods of inducing bradycardiaxe2x80x94for example, by ingestion of beta blockers, calcium channel blockers, or selective bradycardia drugsxe2x80x94it may be difficult to avoid unwanted negative ion inotropy and systemic effects of the drugs, particularly if they are used on a chronic basis. However, even with these side effects, beta blocker therapy is highly beneficial to those patients who can tolerate the side effects. Recently published studies by Carson (Progress in Cardiovascular Diseases, Vol 31, No 4, 1999: pp 301-322) reported a 20% reduction in the risk ratio for mortality in patients treated with beta blockers, although patients received little or no improvement in cardiac output.
Brown et al, in an article titled xe2x80x9cLong term bradycardia by electrical pacing: a new method for studying heart rate reduction,xe2x80x9d Cardiovascular Research 1994; 28: pp. 1774-1779, demonstrated the benefits of using pacing to lower heart rate in pigs. The researchers used a method of stimulating both the atrial and ventricular chambers of the heart to reduce heart rates from about 130 beats per minute (bpm) to about 85 bpm. The animals were maintained at the lower rate for about six weeks. Autopsies revealed that myocardial capillary was increased by about 20%. No evidence was found of the cardiac hypertrophy associated with pharmacological methods of reducing bradycardia, either on the basis of heart weight or on estimates of myocyte size.
Bilgutay et al., in an article titled xe2x80x9cVagal Tuning,xe2x80x9d J Cardiovas. Surg. 56(1):71-82 described studies in dogs with right vagal stimulation for treatment of supraventricular arrhythmias, angina pectoris, and heart failure. The experiments involved right vagus nerve stimulation and resulted in a selection of amplitude of 6 to 10 volts, a frequency of 10 pulses per second, and 0.2 msec pulse duration. In all experiments, the coronary flow remained constant. However, the heart rate was decreased 35 to 50 percent. The increase in percentage of coronary flow per heart beat was found to be 75 to 100 per cent. In another experiment, Bilgutay administered Isuprel to induce tachycardia, which increased heart rate from 170 bpm to 240 bpm. He then stimulated the vagus nerve and reduced the heart rate from 240 bpm to 120 bpm. The ventricular and aortic pressures were unchanged by vagus stimulation, whereas the systole and diastole were prolonged. These results indicated the contractility of the heart was increased in this model of tachycardia, while the slower rate was maintained, resulting in an increase in cardiac efficiency due to greater stroke output. Although he discussed the potential benefits of treating a failing heart, none of the experiments involved models of heart failure, nor did he anticipate increased capillary growth.
Feliciano et al, in an article titled xe2x80x9cVagal nerve stimulation during muscarinic and beta-adrenergic blockade causes significant artery dilation,xe2x80x9d Journal of the Autonomic Nervous System, 68 (1998), pp. 78-88, demonstrated that vagal nerve stimulation in dogs significantly dilates the coronary arteries and significantly increases coronary artery blood flow. Stimulation was performed at frequencies of 10, 15, 20, and 30 Hertz (Hz). In these studies, the muscarinic and beta-adrenergic receptors were blocked with atropine and propranolol.
Heart rate was controlled at normal rates by pacing. Feliciano did not demonstrate artery dilation in normal conditions, without atropine, propranolol and rate stabilization by pacing, nor did he demonstrate an increase in capillary growth.
Vagus stimulation of the left cardiac branch of the vagus nerve to lower ventricular heart rate in the presence of atrial fibrillation is described by Geddes et. al. in U.S. Pat. No. 5,690,681, and the more recently issued U.S. Pat. No. 5,916,239. As disclosed in the ""681 patent, a closed loop, variable frequency vagal stimulation apparatus was used to control ventricular rate during atrial fibrillation. The apparatus included means for stimulating a vagal nerve at a stimulation frequency which was varied automatically in response to sensed conditions, and a controller having an output connected to the stimulating means. The latter included means for automatically and continuously adjusting the vagal stimulation frequency as a function of the difference between actual and desired ventricular excitation rates.
The apparatus of the ""681 patent was stated to automatically control ventricular rate by vagal stimulation, to minimize pulse deficit during atrial fibrillation. The arterial pulse rate was detected and the ventricular excitation rate and arterial pulse rate were compared. The vagal stimulation frequency was automatically adjusted as a function of the difference between the ventricular excitation rate and the arterial pulse rate.
A number of patents describe various methods of vagus stimulation for the control of ventricular arrhythmias. U.S. Pat. No. 5,203,326 to Collins discloses a pacemaker which detects a cardiac abnormalityxe2x80x94a pathologic high ratexe2x80x94and responds with pacing combined with vagus nerve stimulation, to reduce the heart rate from the tachyrhythmia rate to the normal rate. U.S. Pat. No. 5,330,507 to Schwartz describes stimulation of the right or left vagus nerve in response to a ventricular rate exceeding a predetermined threshold characteristic of tachycardia.
European Pat. No. 688577A1 to Holmstrom describes stimulation of the parasympathetic nervous system in the neck in response to detection of a supraventricular arrhythmia. The vagus nerve is a parasympathetic nerve. U.S. Pat. No. 5,700,282 to Zabara describes a process s for monitoring the heart to detect arrhythmias and simultaneous stimulation of the vagus and cardiac sympathetic nerves to stabilize the heart rhythm. U.S. Pat. No. 5,658,318 to Stroetmann describes detecting a state of imminent cardiac arrhythmia from nerve activity signals and administering antiarrhythmia therapy. U.S. Pat. No. 5,522,854 to Ideker describes detection of the ratio of sympathetic to parasympathetic nerve activity and delivering stimulation to afferent nerves u upon detection of a high-risk arrhythmia. None of these patents describe lowering the hear t rate below the normal physiological rate range in heart failure patients to increase growth of capillaries and increase coronary blood flow.
U.S. Pat. No. 5,913,876 to Taylor describes a method of stimulating the vagus nerve near a patient""s heart to momentarily stop the heart in order to perform coronary artery bypass graft surgery.
The present invention is directed to reducing the heart rate in patients suffering from heart failurexe2x80x94a reduction which may be and preferably is to a rate that is lower than the low end of the normal range of the heart rate of a human subjectxe2x80x94to promote and enhance coronary capillary growth and coronary blood flow. This is to be contrasted, for example, with the method and purposes disclosed in the aforementioned ""681 patent, which is primarily concerned with reducing a pathologic rapid heart ratexe2x80x94a rapid ventricular rate in the presence of atrial fibrillationxe2x80x94to a rate within the normal range, by using vagal stimulation.
According to the present invention, an implanted nerve stimulation device, or neurostimulator (sometimes referred to herein simply as a xe2x80x9cdevicexe2x80x9d or a xe2x80x9cstimulatorxe2x80x9d), is employed and programmed to stimulate the vagus nerve at a first prescribed impulse stimulation frequency to reduce the patient""s heart rate, particularly the ventricular rate, toward a heart rate within a desired range. The vagal stimulation frequency is automatically adjusted as a function of the difference between the ventricular excitation rate and the desired ventricular rate. In a typical initial sequence, the implanted device commences to stimulate the vagus nerve at one pulse per second (pps), for example. The stimulation is continued at this frequency for about one minute to allow the ventricular rate to stabilize in the presence of the vagal inputs. Then the vagal stimulation rate is increased, for example to about two pps, and the process continues during another stabilization period. Further change in vagal stimulation frequency is made until the ventricular rate is further reduced and ultimately reaches the desired target range for the rate.
According to an aspect of the invention, the target range is typically set at +/xe2x88x925% to +/xe2x88x9210% of a prescribed target rate, and the amount (or rate) of the increase in the vagal stimulation frequency is preferably reducedxe2x80x94for example, to 0.5 pps, or proportionally lessxe2x80x94as the ventricular rate approaches the target rate range. If the ventricular rate falls below the target rate range, this condition is detected and the vagal stimulation frequency is thereupon automatically reduced or vagal stimulation is entirely inhibited, i.e., ceased, depending upon the extent of the deficit. A damped feedback loop with hysteresis can be used to maintain the frequency of stimulation of the vagus nerve at a level just sufficient to substantially sustain the ventricular rate at the target rate or at least within the target rate range, for example. Alternatively, other types of controllers and control mechanisms may be employed.
As an alternative method, the stimulator may be programmed to reduce the ventricular rate on a periodic basis, by concomitantly and proportionally increasing the vagal stimulation frequency, such as for a period of one hour at the preselected reduced ventricular rate, followed by a period of one hour at the patient""s normal resting rate range. This type of alternating reduced heart rate/normal heart rate therapy may be useful for those patients that initially have difficulty tolerating the lowered heart rate. Further, the ON/OFF times (of reduced rate/normal rate) may be selected from a range of minutes to hours or days.
According to another important aspect of the invention, an activity sensor such as an accelerometer may be incorporated within or associated with the stimulator to detect physical activity by the patientxe2x80x94even merely a change in position, or slow walkingxe2x80x94to trigger either an inhibition of the vagal stimulation, or an adjustment of the vagal stimulation frequency to produce a higher ventricular target rate. In this way, the patient receives the benefit of a more physiologically appropriate higher heart rate during periods of physical activity or exercise. When the patient ceases the physical activity, that condition is detected by the activity sensor and, in response, the stimulation parameters are returned to a level that will ultimately lower the rate to below the resting heart rate range. For a patient experiencing heart failure, this is the reduced ventricular rate according to the invention.
If permitted by the attending physician, the patient may be given a modicum of control over the therapy to adjust the vagal stimulation rate, and thus the heart rate, according to the state of physical activity of the patientxe2x80x94i.e., whether the patient is in a state of rest or engaging in some form of physical activity, even slight. Toward that end, the stimulator device may be implemented, for example, by incorporating in it instead of or in addition to an activity sensor (e.g., an accelerometer), a reed switch which is operable by an external magnet wielded by the patient. When the patient places the magnet over the implant site of the stimulator, the switch operates, for example, to either inhibit vagal stimulation (for increased heart rate when the patient is about to embark in some physical activity) or to initiate vagal stimulation (for reduced heart rate when the patient is entering a state of rest), according to the specific manner in which the device is implemented to respond to operation of the switch.
A different heart rate target and/or rate range may be programmed in the device for magnet-activation, from the heart rate target or rate range selected for the ongoing or prophylactic operation of the stimulator, or from even the activity sensor-triggered target. Additionally, the programming may be devised to initiate a fall-back rate from the elevated heart rate induced by the initial patient-initiated activation, for a more physiologically appropriate heart rate decline when the patient ceases the activity, upon the next patient initiated activation in an activation sequence.
According to a feature of the invention, the device may also be programmed for different heart rate targets or target ranges during daytime and nighttime hours, or otherwise according to the circadian rhythm of the patient, to recognize the normally lower heart rate during sleep or slumber than the rate experienced when the patient is awake.
Therefore, it is a principal object of the present invention to provide a simple method and device by which the heart rate of a patient suffering from heart failure may be reduced by vagal stimulation to a rate which will sustain life but which is below the low end of the normal heart rate range of the patient. It is a related object of the invention to provide such reduction in heart rate through vagal stimulation, with a view to increase myocardial capillary growth, to enhance coronary blood flow, and to increase cardiac output over a sustained period of time.
Another object of the invention is to selectively lower the heart rate of heart failure patients by vagal stimulation in a gradual manner to a rate within a predetermined target rate range below the low end of the normal rate range, and to maintain the heart rate within that target rate range during periods of rest or substantial inactivity of the patient, to produce an increase in coronary blood flow.
Still another object of the invention is to provide for heart rate reduction in heart failure patients by means of vagal stimulation, with allowance for adjustment of the reduced rate as necessary when the patient is engaged in periods of physical activity by either sensing the activity and inhibiting or changing the vagal stimulation accordingly, or by patient-actuated inhibition.
Still another object of the invention is to limit the heart rate in periods of physical activity to a rate which is both safe and appropriate for the heart failure patient.